Innovative lipoplexes formulations with enhanced siRNA efficacy for cancer treatment: Where are we now?

Over the past two decades, RNA interference has become an extensively studied mechanism to silence gene and treat diseases including cancer. siRNA appears as a promising strategy that could avoid some side effects related to traditional chemotherapy. Considering the weak stability of naked siRNA in blood, vectors like cationic liposomes or Lipid Nanoparticles (LNPs) are widely used to carry and protect siRNA until it reaches the tumor targeted. Despite extensive research, only three RNAi drugs are currently approved by the Food and Drug Administration, including only one LNP formulation of siRNA to treat hereditary ATTR amyloidosis. This shows the difficulty of lipoplexes clinical translation, in particular in cancer therapy. To overcome the lipoplexes limitations, searches are made on innovative lipoplexes formulations with enhanced siRNA efficacy. The present review is focusing on the recent use of pH-sensitive lipids, peptides and cell-penetrating peptides or polymers. The incorporation of some of these components in the lipoplex formulation induces a fusogenic property or an enhanced endosomal escape, an enhanced cellular uptake, an enhanced tumor targeting, an improved stability in the blood stream ...These innovations appear critical to obtain an efficient siRNA accumulation in tumor cells with effective antitumor effect considering the complex tumor environment.

Automated summary

RNA interference is a promising mechanism for gene silencing and disease treatment, but the stability of siRNA in blood is a challenge. Lipoplexes and LNPs are commonly used to deliver and protect siRNA, yet clinical translation remains difficult with only few RNAi drugs approved by the FDA. Innovative formulations incorporating pH-sensitive lipids, peptides, and polymers aim to enhance siRNA efficacy for effective antitumor effects in complex tumor environments.